tbuckley/cabot-search huggingface dataset:
Abstract 1856: Adaptation to dopamine impairs the anti-cancer effect of ONC201 and ONC206
Authors: Yiqun Zhang, Wafik S. El-Deiry
Journal: Cancer Research (2022)

Abstract ONC201 (originally discovered as TRAIL-Inducing Compound #10 or TIC10) and analogue ONC206 have been found to induce an integrated stress response with suggested primary targets and mechanisms involving agonist activity against mitochondrial ClpP and antagonism of dopamine receptors D2/3 (DRD2/3). We hypothesized that dopamine, the agonist of DRD2, may compete with ONC201 or ONC206 for DRD2/3 and impair the anti-cancer effect of ONC201 or ONC206. We therefore pre-treated cancer cells from different tissue origins including breast cancer, pancreatic cancer, colorectal cancer, lung cancer, GBM, and DIPG with dopamine for 12 hours, 24 hours or 48 hours, respectively, followed by treatment of ONC201 or ONC206 for 72hours. Cell viability was determined by the CellTiter Glo assay. Single treatment with dopamine did not increase cell viability. We observed that 48 hours of pre-treatment with dopamine at 50 μM, 100 μM or 200 μM impaired the cell viability suppression effect of ONC201 at 4 μM and 8 μM, while ONC206 at 0.5 μM, 1 μM and 2 μM led to similar protection for loss of cell viability in pancreatic cancer cells. The impairment of the anti-cancer effect by dopamine was also observed in colorectal cancer cells with 48 hours pre-treatment with dopamine at 50 μM, 100 μM, 200 μM or 400 μM and treatment with ONC201 at 4 μM and 8 μM, or ONC206 at 0.5 μM, 1 μM, or 2 μM. In addition, we treated pancreatic cancer and colorectal cancer cells with ONC212 after 48 hours pre-treatment with dopamine and observed a similar impairment of the anti-cancer effect, even though ONC212 is not a DRD2 antagonist. We pre-treated pancreatic cancer and colorectal cancer cells with specific DRD2 agonist, sumanirole, for 48 hours followed by treatment of ONC201, ONC206, or ONC212 for 72 hours, and no impairment was seen. We pre-treated multiple cancer cell lines with 2 μM or 10 μM dopamine for one week followed by ONC201, ONC206, or ONC212 treatment and performed colony assays. Pre-treatment with dopamine at 10 μM impaired the anti-cancer effect of ONC201 or ONC206 in pancreatic cancer. Pre-treatment with dopamine at 2 μM or 10 μM impaired the anti-tumor effect of ONC201 in GBM cells. By contrast to the cell viability result, no impairment of ONC212 effect from dopamine was seen in pancreatic cancer cells. Western blotting was conducted to investigate whether dopamine pre-treatment impacted signaling pathways reported to be affected by ONC201. Dopamine pre-treatment did not impact changes induced by ONC201 in ATF4, CHOP, DR5, ClpX, clpP, pERK, pAkt and pS6. We are pursuing whether the protective effect of dopamine is due to the agonism of DRD2 or alternative pro-survival mechanisms. Citation Format: Yiqun Zhang, Wafik S. El-Deiry. Adaptation to dopamine impairs the anti-cancer effect of ONC201 and ONC206 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1856.
Universal allogeneic CAR T cells engineered with Sleeping Beauty transposons and CRISPR-CAS9 for cancer immunotherapy
Authors: Jaitip Tipanee, Ermira Samara-Kuko, Thierry Gevaert, Marinee K. Chuah, Thierry VandenDriessche
Journal: Molecular Therapy (2022)

Allogeneic CD19-specific chimeric antigen receptor (CAR) T cells with inactivated donor T cell receptor (TCR) expression can be used as an "off-the-shelf" therapeutic modality for lymphoid malignancies, thus offering an attractive alternative to autologous, patient-derived T cells. Current approaches for T cell engineering mainly rely on the use of viral vectors. Here, we optimized and validated a non-viral genetic modification platform based on Sleeping Beauty (SB) transposons delivered with minicircles to express CD19-28z.CAR and CRISPR-Cas9 ribonucleoparticles to inactivate allogeneic TCRs. Efficient TCR gene disruption was achieved with minimal cytotoxicity and with attainment of robust and stable CD19-28z.CAR expression. The CAR T cells were responsive to CD19+ tumor cells with antitumor activities that induced complete tumor remission in NALM6 tumor-bearing mice while significantly reducing TCR alloreactivity and GvHD development. Single CAR signaling induced the similar T cell signaling signatures in TCR-disrupted CAR T cells and control CAR T cells. In contrast, TCR disruption inhibited T cell signaling/protein phosphorylation compared with the control CAR T cells during dual CAR/TCR signaling. This non-viral SB transposon-CRISPR-Cas9 combination strategy serves as an alternative for generating next-generation CD19-specific CAR T while reducing GvHD risk and easing potential manufacturing constraints intrinsic to viral vectors.
Abstract 5704: IDH2 mutation reduce radiotherapy induced immune response in glioblastoma by affecting micronucleus formation
Authors: Sara Mahmoud Elkashef, Shirony Nicholson, Shane Harding
Journal: Cancer Research (2022)

Abstract DNA methylation is the most abundant epigenetic modification, it plays a critical role in tissue homeostasis, genomic stability, and mitotic fidelity. Isocitrate dehydrogenase genes (IDH1/2) are non-redundantly mutated in several types of cancers including Glioblastoma (GBM), and their mutation induces a DNA hypermethylation phenotype. Radiotherapy (RT), either alone or in combination with other treatments, forms a primary intervention for GBM but the full scope of how IDH1/2 mutations influence this response are not known. In this work, we demonstrate that IDH2 mutation reduces the formation of post-RT micronuclei (MN), small DNA bodies in the cytoplasm distinct from the primary nucleus. Previously, MN has been found to recruit the pattern recognition receptor cGAS to activate an interferon-mediated signalling cascade via STING. We demonstrate that hypermethylation induced by IDH2 mutation does not impact cGAS localization to MN but instead reduces the overall burden of MN which correlates with decreased cGAS-STING mediated transcriptional activation. Mechanistically, IDH2 mutation drives centromeric hypermethylation which stabilizes kinetochore assembly and the fidelity of mitotic chromosome segregation post radiation. We also demonstrate that a reduction of MN formation in IDH2 mutant tumors reduces synergy between RT and immune checkpoint blockade in murine glioma models. Together our data suggest that metabolic alterations in cancers directly influence mitotic fidelity and response to RT with important implications for combination treatments that capitalize on synergy with the innate cellular signalling toward the adaptive immune system. Citation Format: Sara Mahmoud Elkashef, Shirony Nicholson, Shane Harding. IDH2 mutation reduce radiotherapy induced immune response in glioblastoma by affecting micronucleus formation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5704.
Abstract 343: New derivatives of 1,3-dioxoisoindoline: Potential breast cancer therapeutics that are S6K1 inhibitors
Authors: Satyendra Kumar, Rajesh Komati, Shahensha Shaik, Melyssa Bratton, Linh Tran, Rion Sam, Elijah Johnson-Henderson, Breyanah Graham, Christopher WIlliams, Jayalakshmi Sridhar
Journal: Cancer Research (2022)

Abstract Currently, more than 3.8 million women in the United States are diagnosed with breast cancer which is the second leading cause of cancer-related death in women. The correlation of the ribosomal protein S6 kinase 1 (S6K1) activity and breast cancer is evident from the amplification of S6K1 localized chromosomal region 17q23 in 20% of primary breast cancers. S6K1 is a conserved serine/threonine protein kinase, is the principal kinase effector downstream of the PI3K/mTOR regulatory signaling pathway. Over-expression of S6K1 has been associated with cell transformation and elevated proliferation rates in tumors, poor prognosis and an increased risk of local recurrence. S6K1 has been found to play an important role in the progression of ER-positive (ER+) breast cancer, HER2 positive (HER2+) breast cancer and node-negative premenopausal breast cancer. Inhibition of this kinase can prove to be beneficial for the treatment of several types of breast cancer. Our group has identified new molecules that are derivatives of 6-amido-4-aminoisoindoline-1,3-dione core structure as S6K1 inhibitors with low micromolar inhibition potency (IC50 = 2-5 μM). These compounds also inhibited the growth of HER2+ (SKBR3 and HER2Δ16), ER+ and triple negative breast cancer cells (MDA-MB-231 and MDA-MB-468) with a range of EC50 values (2 - 2000 μM). The EC50 values of growth inhibition of these compounds varied by the type of breast cancer cells and were in direct correlation with the expression levels of S6K1 in those cell lines. These results clearly indicate that high efficacy S6K1 inhibitors can function as potential therapeutics for multiple types of breast cancer. Future work involves in-vivo studies to understand the efficacy and pharmacokinetics of the three compounds. Citation Format: Satyendra Kumar, Rajesh Komati, Shahensha Shaik, Melyssa Bratton, Linh Tran, Rion Sam, Elijah Johnson-Henderson, Breyanah Graham, Christopher WIlliams, Jayalakshmi Sridhar. New derivatives of 1,3-dioxoisoindoline: Potential breast cancer therapeutics that are S6K1 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 343.
Abstract 113: Investigating the role of high mobility group a2 (HMGA2) truncated isoform in promoting oxidative stress in PCa cells
Authors: Taaliah Campbell, Ohuod Hawsawi, Nathan Bowen, Valerie Odero-Marah
Journal: Cancer Research (2022)

Abstract Prostate cancer (PCa) is one of the most commonly diagnosed malignancies among men worldwide and remains the second leading cause of cancer related death in the United States. Oxidative stress has been shown to be increase in several cancers including prostate cancer. In fact, oxidative stress in prostate cancer is suggested to be a direct result of cell exposure to reactive oxygen species (ROS). High mobility group A 2 (HMGA2), a non-histone protein, is an oncogene that is up-regulated in several cancers. This protein has ability to undergo chromosomal rearrangement and alternative splicing, causing its full length/wild type HMGA2 (HMGA2-WT) to become the truncated losing its 3’UTR leading to the generation of HMGA2 truncated (HMGA2-TR). We have previously shown HMGA2-WT’s involvement in epithelial mesenchymal transition (EMT), however, the functional role of HMGA2-TR has not yet been dissected. We hypothesize that truncated HMGA2’s involvement with oxidative stress leads to prostate cancer progression. We analyzed the baseline expression of wild-type vs.truncated HMGA2 in prostate patient tissue and cells lines by real-time PCR and western blot analyses. Prostate cancer patient tissue and some cell lines expressed increasing amounts of both wild-type and truncated HMGA2with increasing tumor grade, when compared to normal epithelial cells. RNA-Seq analysis of LNCaP prostate cancer cells stably overexpressing HMGA2-WT, HMGA2-TR, or empty vector (Neo) control revealed thatHMGA2-TR cells display increased oxidative stress compared to HMGA2-WT or Neo control cells. This was also confirmed by analysis of basal reactive oxygen species (ROS) levels, and the ratio of GSH/GSSG andNADP/NADPH utilizing metabolomics. Additionally, proteomic analysis showed that HMGA2-TR protein interacted with several proteins, including a cytoplasmic stress granule protein G3BP1 that responds to oxidative stress. Transient knockdown of G3BP1 increased ROS in HMGA2-TR cells. These studies may therefore uncover novel role for truncated HMGA2 in oxidative stress. Acknowledgements: These studies were supported by the NIH/NIMHD/RCI Grant #5G12MD007590-31,NIH/NIGMS/RISE Grant #5R25GM060414 Citation Format: Taaliah Campbell, Ohuod Hawsawi, Nathan Bowen, Valerie Odero-Marah. Investigating the role of high mobility group a2 (HMGA2) truncated isoform in promoting oxidative stress in PCa cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 113.
Abstract 5093: A predictive biomarker classififier in NSCLC treated with immunotherapy
Authors: Shixin Zhang, Xintong Wang
Journal: Cancer Research (2022)

Abstract Background: Our Study have been focusing on investigating the immune components to increase immunotherapy efficacy and to assist patient stratification for immunotherapy NSCLC patients, we explored predict property of the mutations characteristics with immunotherapy survival benefit and Tumor Immune Microenvironment(TME)characteristics. Methods: A training cohort of 344 immunotherapy NSCLC were obtained from MSK database with Clinical and biological data. intersecting Candidate genes related to survival(p_value &amp;lt; 0.05)with immunity-related genes (IRGs), following an independent cohort of 75 patients with immunotherapy NSCLC was assessed. Applying the same patients RNA-Seq data calculated TME by CIBERSORT from TCGA database. Results: The result divided the patients into two groups: 54 samples in the MT group ( two or more of the 18 candidate genes mutated) and 290 samples in the WT group (less two mutations in the 18 genes).The TMB status frequency in WT_H/L and MT_H/L cohort were 11.9% vs 3.8% and 21.5% vs 62.8%(MT_H vs WT_H, P &amp;lt; 0.01 ; MT_L vs WT_L, P = 0.046 ). Discovery training cohort showed a high Overall Survial for patients with MT group which was 15.7% and 84.3% for WT group( P_value &amp;lt; 0.0001). The genes mutation signature degree of most immune cells (such as CD4\8+ T cells and M1 macrophages \natural killer ) were higher in the MT group. Conclusions: Our study offers genes mutation biomarker for OS prediction and potential addition development of tumor exemption, to be served as a convenient tool for identifying high relapse individuals with immunotherapy NSCLC patients. Citation Format: Shixin Zhang, Xintong Wang. A predictive biomarker classififier in NSCLC treated with immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5093.
Abstract 6242: Association of prostate cancer risk variants with gene expression in prostate stroma
Authors: Chaoran Ma, Yinglu Zhou, Anna Plym, Giuseppe Nicolò Fanelli, Massimo Loda, Lorelei Mucci, Svitlana Tyekucheva, Kathryn Penney
Journal: Cancer Research (2022)

Abstract Background: Prostate cancer genome-wide association studies have identified &amp;gt;260 germline risk variants which provide strong risk prediction for prostate cancer. Functional interpretation and biological mechanisms of these risk variants are not always clear. Many of the prostate cancer risk variants are expression quantitative trait loci (eQTLs), but studies have mostly been performed in tumor or epithelial-enriched normal prostate tissue. Given emerging evidence supporting that stroma contributes to the carcinogenic process, we examined the associations of prostate cancer risk variants with the expression of genes in prostate stroma. Methods: We generated mRNA expression data for 13,577 genes with the Illumina TruSeq RNA Exome library preparation kit from stromal samples in specimens from participants of the Health Professionals Follow-up Study and Physicians’ Health Study cohorts. Specifically, we profiled 172 stromal samples adjacent to tumor and 86 paired stroma distant from tumor. We included 264 prostate cancer risk variants genotyped data and imputed using a common reference panel (1,000 Genomes Phase I release). We performed cis- (≤1 Mb from the SNP (single nucleotide polymorphism) to the gene) and trans- eQTL analyses using a linear regression model in the R package Matrix eQTL. Results: Thirty-four SNPs were significantly (P &amp;lt; 0.01) associated with cis-expression of 41 nearby genes in prostate stroma adjacent to tumor, and 41 SNPs with 52 nearby genes for stroma distant from tumor. Genome-wide, 86 SNPs were significantly (FDR &amp;lt; 0.10) associated with the expression of 126 genes in stroma adjacent to tumor, and 64 SNPs with 291 genes for stroma distant from tumor. Conclusions: This is the first study to comprehensively examine associations between prostate cancer risk variants and gene expression in prostate stroma. We observed some previous reported associations but also novel associations which may suggest genes that contribute to prostate cancer risk within the stromal tissue. Identifications of eQTLs within prostate stroma may suggest potential mechanisms in specific cell types for their effect on disease. Citation Format: Chaoran Ma, Yinglu Zhou, Anna Plym, Giuseppe Nicolò Fanelli, Massimo Loda, Lorelei Mucci, Svitlana Tyekucheva, Kathryn Penney. Association of prostate cancer risk variants with gene expression in prostate stroma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6242.
Abstract 1850: Characterizing senescence response to PARP inhibition may provide opportunities for enhanced efficacy through combinations with senolytic agents
Authors: Alan P. Lombard, Wei Lou, Christopher P. Evans, Allen C. Gao
Journal: Cancer Research (2022)

Abstract Background: Inhibition of poly (ADP-ribose) polymerase (PARP) is an exciting treatment strategy recently approved for prostate cancer patients with homologous recombination repair defects. Despite this advance in the field, it remains unclear how PARP inhibitor (PARPi) sensitive cells respond to treatment. We previously demonstrated that treatment with the PARPi olaparib induces not only cell death, but also G2/M arrested senescence characterized by activation of the p53 signaling pathway. We hypothesize that targeting PARPi induced senescence may provide a means to enhance the efficacy of PARPi treatment. In our current work, we sought to 1) understand whether senescence induction is a generalized response to all PARPi’s and 2) characterize senescence induction to guide the development of novel treatment strategies combining a PARPi with a senolytic drug. Methods: PARPi sensitive LNCaP and C4-2B prostate tumor cells were treated with olaparib, rucaparib, niraparib, or talazoparib for 5 days to induce senescence. Both vehicle treated and quiescent cells (LNCaP and C4-2B cultured in FBS-low (0.2%) conditions) were used as controls. Cell viability, flow cytometry, and beta-galactosidase activity assays tested response to PARPi’s. Western blot was used to detect PARP activity, apoptosis, and DNA damage response. RNA-sequencing was performed to characterize senescence induced signaling alterations. Results: We found that exposure to rucaparib, niraparib, and talazoparib all induce a robust G2/M arrested senescence response in LNCaP and C4-2B cells, suggesting that senescence induction is a class effect of PARPi’s. PARPi induced senescence is characterized by activation of the p53 signaling pathway and significantly increased expression of the cyclin-dependent kinase inhibitor p21. Furthermore, PARPi induced senescence is distinct from quiescence, suggesting that response to PARP inhibition is phenotypically different from a more general growth arrest. RNA-sequencing revealed several signaling changes associated with senescence which may provide novel treatment opportunities. Conclusions: Senolytics are a class of drugs thought to specifically target senescent cells. Our results demonstrate that PARPi’s induce senescence. Future work will be directed at further characterizing PARPi induced senescence, leading to rationally selected senolytic drug combinations which may enhance the efficacy of PARPi therapy. Citation Format: Alan P. Lombard, Wei Lou, Christopher P. Evans, Allen C. Gao. Characterizing senescence response to PARP inhibition may provide opportunities for enhanced efficacy through combinations with senolytic agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1850.
Abstract 2398: The tobacco cembranoid β-cembrenediol as promising prostate cancer recurrence suppressor lead
Authors: Ethar A. Mudhish, Abu Bakar Siddique, Khaldoun S. Abdelwahed, Judy A. King, Khalid A. El Sayed
Journal: Cancer Research (2022)

Abstract Prostate cancer (PC) is the second leading cause of men death in the US, annually killing &amp;gt;34,000 men. Despite progress in early PC diagnosis and treatment, many patients have locally and distant disease recurrence. Therapeutic androgens deprivation have limited curative potential and associated with severe side effects and rapid resistance development justifying the dire need for discovery of novel recurrence inhibitors. (1S,2E,4R,6R,-7E,11E)-2,7,11-cembratriene-4,6-diol (β-CBT) and its 4-epi-analog (α-CBT) are the precursors to key flavor ingredients in leaves of most Nicotiana species. Nearly 40-60% of β- and α-CBT are purposely degraded during the commercial tobacco fermentation. Earlier, we reported the lack of β-CBT cytotoxicity below 50 µM while at 50 nM it reversed the calcitonin-stimulated decrease in transepithelial resistance and increased paracellular permeability in PC-3M PC cells. β-CBT also proven to stimulate tight junction formation between PC-3M cells, producing a tighter intercellular barrier. β-CBT 10-50 nM potently inhibited the calcitonin-stimulated PC-3M cells invasion in Matrigel assay. This study demonstrates the in vitro β-CBT anti-migratory (wound-healing assay) and anti-clonogenicity (colony-formation assay) activities against five PC cell lines, including the metastatic castration-recurrent human prostate cancer (mCRPC) CWR-R1ca. Meanwhile, β-CBT potently suppressed the in vivo locoregional and distant recurrences after the primary tumor surgical excision of the tumor formed by engrafting the human metastatic prostate PC-3M-Luc cells at the suprascupular region in male nude mice model. β-CBT treatments prevented organ and significantly suppressed bone metastasis and lacked any major toxicity over the 60-day study course. Therefore, β-CBT emerges as an effective promising PC recurrence and metastasis suppressive lead appropriate for near future use as a prospective nutraceutical. Citation Format: Ethar A. Mudhish, Abu Bakar Siddique, Khaldoun S. Abdelwahed, Judy A. King, Khalid A. El Sayed. The tobacco cembranoid β-cembrenediol as promising prostate cancer recurrence suppressor lead [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2398.